The present invention refers to a new process for the synthesis of tetrahydrothieno[3,2-c]pyridine derivatives, in particular 5-o-chlorobenzyl-4,5,6,7-tetrahydothieno[3,2-c]pyridine and racemic or enantiomerically enriched methyl xcex1-(4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate, and intermediates thereof.
Structure 1, known as Ticlopidine, is an antithrombotic drug with platelet aggregation inhibiting properties as disclosed in U.S. Pat. No. 4,051,141 and U.S. Pat. No. 4,127,580. 
The dextrorotatory enantiomer (Structure 2), bearing the International Non-Proprietary name (INN) Clopidogrel, has the absolute configuration S and is a commercially significant drug with excellent antithrombotic and platelet aggregation inhibiting activity as disclosed in U.S. Pat. No. 4,847,265. 
Similar properties are displayed by the less potent racemic mixture (U.S. Pat. No. 4,529,596).
The enantiomerically enriched compound can be prepared by means of enantioselective synthesis or starting from a racemic mixture of enantiomers in conjunction with a resolution process.
A known process for the preparation of racemic Clopidogrel 2 is based on the nucleophilic displacement of racemic xcex1-halophenylacetic acid derivatives 3 by 4,5,6,7-tetrahydrothieno[3,2c]pyridine 4 as described in U.S. Pat. No. 4,529,596 and U.S. Pat. No. 5,132,435 (Scheme 1). 
The enantiomerically enriched clopidogrel is obtained through the resolution of the racemic mixture of methyl xcex1-(4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate 2 with R-camphorsulfonic acid as described in U.S. Pat. No. 4,847,265 and U.S. Pat. No. 5,132,435.
Racemic clopidogrel can also be prepared starting with the Strecker synthesis of xcex1-(2-thienyl)ethylamino-o-chlorophenylacetonitrile 6 as shown in Scheme 2. Hydrolysis of the nitrile followed by esterification leads to methyl xcex1-(2-thienyl)ethylamino-o-chlorophenylacetate 8. This in turn generates the tetrahydrothieno[3,2-c]pyridine bicyclic system by reacting with a formylating agent (e.g. paraformaldehyde) under acidic conditions. The process is disclosed in WO 98/51682, WO 98/51689 and WO 98/51681. 
According to these patents (WO 98/51682 WO 98/51689, WO 98/51681), the same reaction scheme can be applied to the preparation of dextrorotatory clopidogrel in combination with the resolution, one of the intermediates. Thus, xcex1-(2-thienyl)ethylamino-o-chlorophenylacetonitrile 6, xcex1-(2-thienyl)ethylamino-o-chlorophenylacetamide 7 and methyl xcex1-(2-thienyl)ethylamino-o-chlorophenylacetate 8 are resolved with enantiomerically enriched camphorsulfonic acid, tartaric acid and camphorsulfonic acid respectively. Each of these enantiomerically enriched intermediates can be transformed stereospecifically to dextrorotatory clopidogrel without significant racemization. Notably, the stereospecificity of the last step in Scheme 2 is also disclosed in U.S. Pat. No. 5,204,469.
An alternative process for the preparation of the dextrorotatory clopidogrel starts with enantiomerically enriched methyl o-chlorophenylglycine 10 and alkali 2-thienylglycidate 9 in the presence of a borohydride reducing agent as reported in WO 98/39322 (Scheme 3). 
In a different approach, dextrorotatory clopidogrel can be obtained starting from enantiomerically enriched (R)-sulphonyloxyacetic ester derivatives 11 and 4,5,6,7-tetrahydrothieno[3,2c]pyridine 4 as disclosed in WO 99/18110. The same publication documents the reaction of the methyl (R)-xcex1-tosyloxy-o-chlorophenylacetate 11 with 2-(2-thienyl)ethylamine 12 to result in methyl (S)-xcex1-(2-(2-thienyl)ethylamino-o-chlorophenylacetate 8. This in turn generates enantiomerically enriched clopidogrel by reaction with a formylating reagent under acidic conditions. (Scheme 4). 
Literature precedent for ticlopidine (J. P. Maffrand, R. Boigegrain, Heterocycles, 1979, 12, 1479; FR 2,424,278) shows that (2-thienyl)ethylene oxide 14 reacts with o-chlorobenzylamine to provide the desired N-(2-(2-thienyl)-2-hydroxyethyl)-o-chlorobenzylamine in low yield due to lack of regioselectivity in the epoxide ring opening (Scheme 5). 
Experiment has shown that further complication arise from the limited stability of the (2-thienyl)ethylene oxide under vacuum distillation and ambient temperature storage conditions. As expected, the extension of this approach to the synthesis of clopidogrel was bridled by lower chemical yield and lack of regioselectivity in the epoxide ring opening step. Moreover, the subsequent thermal rearrangement step leading to the 4,5,6,7-tetrahydrothieno[3,2-c]pyridine skeleton (J. Heterocyclic Chem., 1976, 13, 1347) failed to provide the target hydroxyclopidogrel intermediate under the reported conditions. In conclusion, the use of the (2-thienyl)ethyleneoxide as an intermediate is technically unfeasible while the rearrangement step is substrate dependent and suffers from lack of generality.
It is therefore an object of the present invention to provide an improved process for the preparation of tetrahydrothieno[3,2-c]pyridine derivatives, in particular 5-(2-chlorobenzyl)-4,5,6,7-tetrahydothieno[3,2-c]pyridine and racemic or enantiomerically enriched methyl xcex1-(4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl-o-chlorophenylacetate with inexpensive reagents and in good yields.
It is also an object of the present invention to identify novel intermediates which are useful in the manufacture of the above said compounds.
Further and other objects of the invention will be realised from the summary of invention and examples illustrating the invention.
The present invention provides an improved process for the preparation of a racemic and enantiomerically enriched 4,5,6,7- tetrahydrothieno[3,2-c]pyridines of general formula I 
The compound of the general formula I is prepared (Scheme 6) by reducing the compound of formula II with suitable reducing agents, known to those skilled in the art, to a mixture of diastereoisomeric compounds of formula III which are reacted with formaldehyde or any chemical equivalent thereof to yield the compound of formula IV. The compound of formula IV is further rearranged in a suitable solution to produce the compound of formula V which upon reduction (by a suitable reducing agent) provides an enantiomerically enriched or racemic mixture of tetrahydrothieno[3,2-c]pyridine of formula I. 
In the general formulae I and V, X can be hydrogen, carboxyl, alkoxycarbonyl, aryloxycarbonyl, nitrile or carbamoyl of formula 
wherein R1 and R2 can be individually or simultaneously hydrogen, alkyl or part of a heterocyclic structure; Y can be hydroxyl, alkanoyloxy, aroyloxy, as well as carbonate derivatives of formula xe2x80x94OCOOR3 or carbamate derivatives of formula xe2x80x94OCONR4R5 wherein R3 can be substituted or unsubstituted alkyl or aryl; R4 and R5 can be individually or simultaneously substituted or unsubstituted alkyl, aryl or cycloalkyl; Z can be hydrogen, halogen, alkyl, aryl, aryloxy or alkoxy group.
The compound of formula II in its racemic or enantiomerically enriched form is obtained through the reaction of a racemic or enantiomerically enriched primary amine of general formula 
with an xcex1 substituted 2-acetylthiophene derivative of general formula 
where X and Z have the same meaning as above and LG is a leaving group such as halogen, arysulphonyloxy, aryloxy, sulphonate, alkyloxy and its derivatives or activated aryl. Other obvious synthetic chemical equivalents of the phenylglycine counterpart, such as various salts as well as aliphatic or aromatic esters, amides, nitrile or free carboxyl group are also included in the present invention. The reaction may be carried out in an aromatic solvent (e.g. toluene and the like), polar aprotic solvents (e.g. dimethylformamide, hexamethylphosphoramide, ketones such as acetone, MEK, MIBK and the like), polar protic solvents (e.g. methanol, ethanol, propanol, butanol, n-butanol, isobutanol, n-procanol isopropanol, and the like) or conceivable mixtures thereof.
The process according to one aspect of the present invention improves the previously reported synthesis of ticlopidine and extends the scope of the synthetic sequence to the structurally related clopidogrel.
The process according to a further aspect of the invention circumvents prior art drawbacks and is exemplified by (but not limited to) the specific reaction sequence displayed in Scheme 7.
The starting materials, 2-bromoacetylthiophene 18 and methyl o-chlorophenylglycinate 19 can be prepared according to known literature procedures as reported in Bull. Chem. Soc. Jpn. 60, 1159 and J. Am. Chem. Soc. 1999, 121, 4284 respectively. Racemic or enantiomerically enriched methyl 2-o-chlorophenylglycine 19 reacts with 2-bromoacetylthiophene 18 in the Presence of a base which acts as an acid scavenger. 
The reduction of the methyl N-(2-(2-thienyl)-2-oxoethyl)-o-chlorophenylglycinate 20 to the corresponding alcohol results in a mixture of diastereoisomeric alcohols methyl N-(2-(2-thienyl)-2-hydroxyethyl)-o-chlorophenylglycinate 21. Reaction with formaline provides the 5-(2-thienyl)-3-(methoxycarbonyl-o-chlorobenzyl)-1,3-oxazolidine 22. Rearrangement of the 5-(2-thienyl)oxazolidine 22 derivative occurs in dry HCl/DMF solution to produce the desired methyl xcex1-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylglycinate 23. Finally, the alcohol is reduced to the racemic 24 or dextrorotatory clopidogrel 2 by direct dehydroxylation, e.g. treatment with stannous chloride under acidic conditions. Alternatively, derivatization of hydroxyl group to a leaving group followed by reduction or stepwise elimination/reduction of the corresponding 4,5-dihydropyridyl intermediate is conducive to the synthesis of racemic 24 or dextrorotatory clopidogrel 2. Treatment with carbonyl diimidazole, heating, followed by sodium borohydride reduction is provided as a non-limiting example.
The use of o-chlorobenzylamine instead of the methyl glycinate 19 in Scheme 7 provides the process for the synthesis of Ticlopidine.
According to a further aspect of the invention, there are provided novel compounds of formulae 22, 21 and 20 which can be made as a racemic or diasteromeric mixture with set configuration at the carbon adjacent to the nitrogen, as well as its enantiomers either as free base or its salts with Brxc3x6nstead and Lewis acids. Specific compounds arising from the preparation of formulae 22, 21 and 20 include:
5R-(2-thienyl)-3-(1R-methoxycarbonyl-o-chlorobenzyl)-1,3-oxazoline
5R-(2-thienyl)-3-(1S-methoxycarbonyl-o-chlorobenzyl)-1,3-oxazoline
5S-(2-thienyl)-3-(1R-methoxycarbonyl-o-chlorobenzyl)-1,3-oxazoline
5S-(2-thienyl)-3-(1S-methoxycarbonyl-o-chlorobenzyl)-1,3-oxazoline
Methyl N-(2R-(2-thienyl)-2-hydroxyethyl)-2R-o-chlorophenylglycinate
Methyl N-(2R-(2-thienyl)-2-hydroxyethyl)-2S-o-chlorophenylglycinate
Methyl N-(2S-(2-thienyl)-2-hydroxyethyl)-2R-o-chlorophenylglycinate
Methyl N-(2S-(2-thienyl)-2-hydroxyethyl)-2S-o-chlorophenylglycinate
Methyl N-(2-(2-thienyl)-2-oxoethyl)-2R-o-chlorophenylglycinate
Methyl N-(2-(2-thienyl)-2-oxoethyl)-2S-o-chlorophenylglycinate